1. Field of the Invention
This invention relates to the use of alkyl or alkenyl phenols or their pharmaceutically acceptable base salts as aldose reductase inhibitors. More particularly, the invention relates to a method of ameliorating chronic complications arising in a galactosemic or diabetic host by administering to the host a therapeutically effective amount of the foregoing alkyl or alkenyl phenols or their pharmaceutically acceptable base salts as well as to compositions containing the same.
2. Related Art
Aldose reductase, an enzyme in the sorbitol pathway of glucose metabolism, catalyzes the reduction of various aldoses (such as glucose and galactose) to the corresponding polyols (such as sorbitol and glactitol).
In the lens of a galactosemic or diabetic host, the formation of excess sugar polyols followed by the osmotic accumulation of water leads to cataract formation [J. H. Kinoshita et al., Invest. Opthalmod., 13, 713 (1974)]. Thus, as the polyols accumulate to levels high enough to cause hypertonicity, lens fiber swells. This osmotic swelling triggers an electrolyte imbalance in the lens with loss in K.sup.+ and gain in Na.sup.+, accompanied by massive influx of water, which eventually results in lenticular opacity. The lenticular opacity is caused by the microaggregation or precipitation of the normally translucent lenticular proteins. This sequence of events is believed to be the mechanism of cataract formation in a galactosemic or diabetic host.
Alrestatin [AY-22, 284; 1,3-dioxo-1H-benz (de) isoquinoline-2(3H)-acetic acid] has heretofore been reported to successfully prevent galactosemic cataract formation in experimental rats by inhibiting aldose reductase, and therefore, by blocking the sugar polyol accumulations [D. Dvornik, et al., Science, 182, 1146 (1973)].
U.S. Pat. No. 4,348,526 to R. Sarges discloses another aldose reductase inhibitor known as sorbinil (d-6-fluoro-spiro [chroman-4,4'-imidazolidine]-2',5'-dione), which is one of the most potent inhibitors heretofore investigated. Sorbinil is reported to inhibit calf lens aldose reductase at the IC.sub.50 concentration of .about.5.times.10.sup.-7 M.
In the peripheral nerve of a diabetic host, the accumulation of sugar polyols causes a slowing of conduction in nerve fiber. It is this decreased nerve conduction velocity in both sensory and motor nerves which characterizes diabetic neuropathy. It has been demonstrated that alrestatin and sorbinil improve motor nerve conduction velocity (MNCV) in both short and long-term streptozotocin induced diabetes in rats [K. H. Gabbay, Advances in Metabolic Disorders, Suppl. 2, New York, Academic Press, 1973, p. 417; D. R. Tomlinson et al., Diabetes, 33, 470 (1984)].
These aldose reductase inhibitors prevent or reduce unwanted accumulations of galactitol in the lens of galactosemic hosts and of sorbitol in the lens, peripheral nervous cord and kidney of diabetic hosts. Although both alrestatin and sorbinil originally showed promise in effectively controlling diabetic complications such as diabetic cataracts, neuropathy, and retinopathy, etc., in humans, they were found to have significant drawbacks. For example, no improvement was observed with alrestatin administered to diabetic patients suffering from peripheral nerve deterioration [K. H. Gabbay, et al., Metabolism, 28, 471 (1979)]. Furthermore, no beneficial effect was observed with sorbinol in a similar study [I. G. Lewin, et al., Diabetologia, 26, 445 (1984)]. Accordingly, a search continues to find improved inhibitors of aldose reductase which would be therapeutically useful in the treatment of diabetes-associated chronic complications.